Solid state forms of tapentadol salts

ABSTRACT

Provided herein are novel solid state forms of tapentadol salts, process for their preparation, pharmaceutical compositions, and method of treating thereof. The tapentadol salts include an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt, or a salicylate salt.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation of U.S. application Ser. No.12/886,680, filed Sep. 21, 2010, which claims the benefit of priority toIndian provisional application No. 2287/CHE/2009, filed on Sep. 22,2009, which are incorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to novel solid state forms of tapentadolsalts, a process for their preparation, pharmaceutical compositions, andmethods of treating thereof.

BACKGROUND

U.S. Reissue Pat. No. USRE39593 discloses a variety of1-phenyl-3-dimethylaminopropane compounds, processes for theirpreparation, pharmaceutical compositions comprising the compounds, andmethod of use thereof. These compounds have the utility as analgesicactive ingredients in pharmaceutical compositions. Among them,tapentadol hydrochloride,3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenolhydrochloride, is a centrally-acting analgesic with a unique dual modeof action as an agonist at the g-opioid receptor and as a norepinephrinereuptake inhibitor. Tapentadol hydrochloride is represented by thefollowing structural formula:

Various processes for the preparation of tapentadol, its enantiomers andrelated compounds, and their pharmaceutically acceptable salts aredisclosed in U.S. Pat. Nos. 6,248,737 and 6,344,558; and PCT PublicationNos. WO 2004/108658, WO 2005/000788, WO 2008/012046, WO 2008/012047 andWO 2008/012283.

U.S. Pat. No. 6,248,737 (herein after referred to as the '737 patent)discloses processes for the preparation of tapentadol or apharmaceutically acceptable salt thereof. While the '737 patent mentionsthat some of the disclosed compounds can form salts with physiologicallyacceptable acids, for example, hydrochloric acid, hydrobromic acid,sulfuric acid, methanesulfonic acid, formic acid, acetic acid, oxalicacid, succinic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid and/or aspartic acid, only thehydrochloride salt had been prepared and isolated.

According to the '737 patent, tapentadol is prepared by the reaction of(−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-olhydrochloride with thionyl chloride to produce(−)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylaminehydrochloride, followed by subsequent removal of the ‘Cl’ substituent bytreatment with zinc borohydride, zinc cyanoborohydride or tincyanoborohydride, to produce(−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylaminehydrochloride. The (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride is then converted to(−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol(tapentadol) by reacting with concentrated hydrobromic acid at reflux.

U.S. Patent Application No. 2007/0213405 (hereinafter referred to as the'405 application) discloses two crystalline polymorphs (Form A & Form B)of (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenolhydrochloride (tapentadol hydrochloride), and characterizes them bypowder X-ray diffraction (P-XRD), Infra Red spectroscopy (IR), RAMANspectroscopy and crystal structure analysis. The '405 applicationfurther teaches that the procedure described in example 25 of U.S. Pat.No. 6,248,737 and U.S. Pat. No. 6,344,558 as well as EP 693475 B1produces crystalline Form B of tapentadol hydrochloride.

U.S. Patent Application No. 2009/0149534 (hereinafter referred to as the'534 application) discloses three crystalline modifications(modifications A, B & C) of tapentadol base, processes for theirpreparation, and characterizes the modifications by powder X-raydiffraction (P-XRD) pattern and RAMAN spectroscopy.

There remains a need for novel solid state forms of tapentadol salts.

SUMMARY

In one aspect, provided herein are novel solid state forms of atapentadol salt, wherein the salt is an L-(−)-camphorsulfonate salt, adibenzoyl-(L)-tartrate salt, a dibenzoyl-(D)-tartrate salt, a malatesalt, a maleate salt or a salicylate salt.

In another aspect, tapentadol salts in a crystalline form are provided.In yet another aspect, tapentadol salts in an amorphous form areprovided. In still another aspect, the solid state forms of tapentadolsalts exist in an anhydrous and/or solvent-free form or as a hydrateand/or a solvate form.

In another aspect, encompassed herein is a process for preparing a solidstate form of a tapentadol salt comprising contacting tapentadol freebase with an acid in a suitable solvent under suitable conditions toproduce a reaction mass, and isolating the solid state form oftapentadol acid addition salt, wherein the acid addition salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartratesalt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

In another aspect, provided herein is a method for treating a patientsuffering from severe acute pain; comprising administering a solid stateform of tapentadol salt, or a pharmaceutical composition that comprisesthe solid state form of tapentadol salt along with pharmaceuticallyacceptable excipients, wherein the salt of tapentadol is anL-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, adibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

In another aspect, provided herein is a pharmaceutical compositioncomprising a solid state form of tapentadol salt as disclosed herein,and one or more pharmaceutically acceptable excipients.

In still another aspect, provided herein is a pharmaceutical compositioncomprising a solid state form of tapentadol salt made by the processdisclosed herein, and one or more pharmaceutically acceptableexcipients.

In still further aspect, encompassed herein is a process for preparing apharmaceutical formulation comprising combining any one of the solidstate forms of tapentadol salts disclosed herein with one or morepharmaceutically acceptable excipients.

In another aspect, the solid state forms of tapentadol salts disclosedherein for use in the pharmaceutical compositions have a D₉₀ particlesize of less than or equal to about 500 microns, specifically about 1micron to about 300 microns, and most specifically about 10 microns toabout 150 microns.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol L-(−)-camphorsulfonate salt.

FIG. 2 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol L-(−)-camphorsulfonatesalt.

FIG. 3 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol dibenzoyl-(L)-tartrate salt.

FIG. 4 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol dibenzoyl-(L)-tartratesalt.

FIG. 5 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol dibenzoyl-(D)-tartrate salt.

FIG. 6 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol dibenzoyl-(D)-tartratesalt.

FIG. 7 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol malate salt.

FIG. 8 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol malate salt.

FIG. 9 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol maleate salt.

FIG. 10 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol maleate salt.

FIG. 11 is a characteristic Powder X-ray Diffraction (XRD) pattern ofsolid state form of tapentadol salicylate salt.

FIG. 12 is a characteristic Differential Scanning calorimetric (DSC)thermogram of solid state form of tapentadol salicylate salt.

DETAILED DESCRIPTION

Solid state forms of tapentadol salts, except the hydrochloride salt,have not been reported, isolated, or characterized in the literature.The present inventors have surprisingly and unexpectedly found that someof the acid addition salts of3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol, i.e.,tapentadol salts, specifically, L-(−)-camphorsulfonate,dibenzoyl-(L)-tartrate salt, dibenzoyl-(D)-tartrate salt, malate,maleate and salicylate salts, can be isolated as solid state forms.

It has also been found that the solid state forms of tapentadol saltsare useful intermediates in the preparation of tapentadol or apharmaceutically acceptable salt thereof in high purity. The solid stateforms of tapentadol salts have good flow properties, and are stable atroom temperature, enhanced temperature, at relative high humidities, andin aqueous media. The novel solid state forms of tapentadol salts aresuitable for formulating tapentadol.

In the formulation of drug compositions, it is important for the activepharmaceutical ingredient to be in a form in which it can beconveniently handled and processed. Convenient handling is important notonly from the perspective of obtaining a commercially viablemanufacturing process, but also from the perspective of subsequentmanufacture of pharmaceutical formulations (e.g., oral dosage forms suchas tablets) comprising the active pharmaceutical ingredient.

Chemical stability, solid state stability, and “shelf life” of theactive pharmaceutical ingredient are important properties for apharmaceutically active compound. The active pharmaceutical ingredient,and compositions containing it, should be capable of being effectivelystored over appreciable periods of time, without exhibiting asignificant change in the physico-chemical characteristics of the activepharmaceutical ingredient, e.g., its chemical composition, density,hygroscopicity and solubility. Thus, in the manufacture of commerciallyviable and pharmaceutically acceptable drug compositions, it isimportant, wherever possible, to provide the active pharmaceuticalingredient in a stable form.

New solid state forms of a pharmaceutical agent can further thedevelopment of formulations for the treatment of illnesses. Forinstance, solid forms of a compound are known in the pharmaceutical artsto affect, for example, the solubility, dissolution rate,bioavailability, chemical and physical stability, flowability,fractability, and compressibility of the compound, as well as the safetyand efficacy of drug products based on the compound.

The discovery of novel salts in solid state form of pharmaceuticallyuseful compounds provides a new opportunity to improve the performancecharacteristics of a pharmaceutical product. It also adds value to thematerial that a formulation scientist can use the same for designing,for example, a pharmaceutical dosage form of a drug with a targetedrelease profile or other desired characteristic.

According to one aspect, provided herein are novel and stable solidstate forms of tapentadol salts, wherein the salt of tapentadol is anL-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, adibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

In one embodiment, the solid state forms of tapentadol salts exist in acrystalline form. In another embodiment, the solid state forms oftapentadol salts exist in an amorphous form. In yet another embodiment,the solid state forms of tapentadol salts exist in an anhydrous and/orsolvent-free form, or as a hydrate and/or a solvate form. Such solvatedor hydrated forms may be present as hemi-, mono-, sesqui-, di- or tri-solvates or hydrates. Solvates and hydrates may be formed as a result ofthe solvents used during the formation of the tapentadol salts becomingembedded in the solid lattice structure. Because formation of thesolvates and hydrates occurs during the preparation of tapentadol salts,formation of a particular solvated or hydrated form depends greatly onthe conditions and method used to prepare the salt. Solvents should bepharmaceutically acceptable.

In one embodiment, the solid state forms of tapentadol salts have thefollowing characteristics, wherein:

-   -   a) the solid state form of tapentadol L-(−)-camphorsulfonate        salt is characterized by one or more of the following        properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 1;        -   ii) a powder X-ray diffraction pattern having peaks at about            3.93, 5.66, 14.94, 16.16 and 21.52±0.2 degrees 2-theta;        -   iii) a powder X-ray diffraction pattern having additional            peaks at about 8.01, 11.36, 14.10, 15.27, 15.91, 16.72,            19.06, 19.88, 21.85, 22.56, 23.92 and 27.12±0.2 degrees            2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 2;    -   b) the solid state form of tapentadol dibenzoyl-(L)-tartrate        salt is characterized by one or more of the following        properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 3;        -   ii) a powder X-ray diffraction pattern having peaks at about            4.83, 5.76, 9.61, 16.08, 17.40 and 17.82±0.2 degrees            2-theta;        -   iii) a powder X-ray diffraction pattern having additional            peaks at about 11.72, 13.26, 14.39, 17.19, 18.14, 18.90,            19.19, 20.88, 21.53, 21.88, 22.43, 22.78, 23.31, 23.53,            24.06, 26.58, 27.26, 27.98, 31.22, 34.75 and 34.96±0.2            degrees 2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 4;    -   c) the solid state form of tapentadol dibenzoyl-(D)-tartrate        salt is characterized by one or more of the following        properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 5;        -   ii) a powder X-ray diffraction pattern having peaks at about            8.52, 9.39, 11.81, 12.28, 13.46, 14.06, 17.77, 17.97, 18.33,            18.79, 19.58 and 20.05±0.2 degrees 2-theta;        -   iii) a powder X-ray diffraction pattern having additional            peaks at about 10.69, 11.61, 14.76, 21.41, 21.66, 22.19,            22.96, 23.23, 24.38, 25.72, 26.42, 27.60, 27.82, 28.29,            28.46 and 30.65±0.2 degrees 2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 6;    -   d) the solid state form of tapentadol malate salt is        characterized by one or more of the following properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 7;        -   ii) a powder X-ray diffraction pattern having peaks at about            9.80, 19.74, 20.27, 22.87 and 24.85±0.2 degrees 2-theta;        -   iii) a powder X-ray diffraction pattern having additional            peaks at about 17.63, 22.56, 26.30, 26.74, 30.67, 31.15,            33.73, 34.12, 35.89, 38.19, 39.27, 41.27 and 43.44±0.2            degrees 2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 8;    -   e) the solid state form of tapentadol maleate salt is        characterized by one or more of the following properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 9;        -   ii) a powder X-ray diffraction pattern having peaks at about            15.31, 16.08, 21.08, 27.95, 28.53 and 29.51±0.2 degrees            2-theta;        -   iii) a powder X-ray diffraction pattern having peaks at            about 19.13, 20.44, 22.90, 24.76, 30.66, 31.06, 31.81,            33.80, 34.84, 35.29, 38.31, 40.26, 40.68 and 43.16±0.2            degrees 2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 10;    -   f) the solid state form of tapentadol salicylate salt is        characterized by one or more of the following properties:        -   i) a powder X-ray diffraction pattern substantially in            accordance with FIG. 11;        -   ii) a powder X-ray diffraction pattern having peak at about            12.42, 12.75, 13.98, 15.37 and 19.81±0.2 degrees 2-theta;        -   iii) a powder X-ray diffraction pattern having peak at about            16.39, 19.31, 21.06, 21.41, 21.98, 24.85, 25.03, 25.45,            26.54 and 27.88±0.2 degrees 2-theta; and        -   iv) a differential scanning calorimetric (DSC) thermogram            substantially in accordance with FIG. 12.

The solid state forms of tapentadol salts are stable, consistentlyreproducible, and are particularly suitable for bulk preparation andhandling. Moreover, the solid state forms of tapentadol salts are usefulintermediates in the preparation of tapentadol free base and itshydrochloride salt in high purity. Specifically, the preparation ofsolid state form of tapentadol dibenzoyl-(D)-tartrate salt isadvantageous since the product can be resolved and purified by removingundesired isomers at final stage, thereby producing tapentadol or apharmaceutically acceptable salt thereof in high enantiomeric andchemical purity.

According to another aspect, there is provided a process for thepreparation of a solid state form of a tapentadol salt, wherein the saltof tapentadol is an L-(−)-camphorsulfonate salt, adibenzoyl-(L)-tartrate salt, a dibenzoyl-(D)-tartrate salt, a malatesalt, a maleate salt or a salicylate salt, comprising:

-   -   a) providing a first solution or a suspension of tapentadol free        base in a solvent, wherein the solvent is water, an alcohol, a        ketone, a nitrile, a polar aprotic solvent, or a mixture        thereof;    -   b) combining the first solution or suspension with an acid to        produce a second solution or suspension containing a tapentadol        acid addition salt, wherein the acid is selected from the group        consisting of L-(−)-camphorsulfonic acid, dibenzoyl-(L)-tartaric        acid, dibenzoyl-(D)-tartaric acid, malic acid, maleic acid and        salicylic acid; and    -   c) isolating and/or recovering the solid state form of the        tapentadol salt from the second solution or suspension obtained        in step-(b).

The process can produce the solid state forms of tapentadol salts insubstantially pure form.

The term “substantially pure solid state form of tapentadol salt” refersto the solid state form of tapentadol salt having a purity of greaterthan about 98 wt %, specifically greater than about 99 wt %, morespecifically greater than about 99.5 wt %, and still more specificallygreater than about 99.9 wt %. The purity is preferably measured by HighPerformance Liquid Chromatography (HPLC). For example, the purity of thesolid state form of tapentadol salt obtained by the process disclosedherein can be about 98% to about 99.95%, or about 99% to about 99.99%,as measured by HPLC.

In one embodiment, the process disclosed herein provides stable solidstate forms of tapentadol salts. The term “stable solid state form”refers to stability of the solid state form under the standardtemperature and humidity conditions of testing of pharmaceuticalproducts, wherein the stability is indicated by preservation of theoriginal solid state form.

In another embodiment, the solid state forms of tapentadol saltsdisclosed herein remain in the same solid state form and are stable,when stored at a temperature of about 25±2° C. and at a relativehumidity of about 55±5% for a period of at least one month.

In still another embodiment, the solid state forms of tapentadol saltsdisclosed herein remain in the same solid state form and are stable,when stored at a temperature of about 25±2° C. and at a relativehumidity of about 55±5% for a period of 3 months.

The term “remains stable”, as defined herein, refers to lack offormation of impurities, while being stored as described hereinbefore.

In one embodiment, the solvent used in step-(a) is selected from thegroup consisting of water, methanol, ethanol, n-propanol, isopropylalcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, isoamylalcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutyl ketone,methyl tert-butyl ketone, acetonitrile, N,N-dimethylformamide,N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

Specifically, the solvent is selected from the group consisting ofwater, methanol, ethanol, isopropyl alcohol, acetone, acetonitrile, andmixtures thereof and more specifically water, methanol, ethanol,isopropyl alcohol, acetonitrile, and mixtures thereof.

Step-(a) of providing a first solution of tapentadol free base includesdissolving tapentadol free base in the solvent, or obtaining an existingsolution from a previous processing step.

In one embodiment, the tapentadol is dissolved in the solvent at atemperature of below about the boiling temperature of the solvent used,specifically at about 20° C. to about 110° C., and more specifically atabout 25° C. to about 80° C.

In another embodiment, step-(a) of providing a suspension of tapentadolfree base includes suspending tapentadol free base in the solvent whilestirring at a temperature of about 0° C. to the reflux temperature ofthe solvent used. In one embodiment, the suspension is stirred at atemperature of about 20° C. to about 110° C. for at least 30 minutes,and more specifically at a temperature of about 25° C. to about 80° C.for about 1 hour to about 10 hours.

The first solution or suspension obtained in step-(a) is optionallystirred at a temperature of about 25° C. to the reflux temperature ofthe solvent used for at least 15 minutes, and specifically at atemperature of about 40° C. to the reflux temperature of the solventused for about 20 minutes to about 5 hours.

As used herein, “reflux temperature” means the temperature at which thesolvent or solvent system refluxes or boils at atmospheric pressure.

The acid in step-(b) may be used directly or in the form of a solutioncontaining the acid and a solvent. The solvent used for dissolving theacid is selected from the group as described above.

Combining of the first solution or suspension with acid in step-(b) isdone in a suitable order, for example, the first solution or suspensionis added to the acid, or alternatively, the acid is added to the firstsolution or suspension. The addition is, for example, carried out dropwise or in one portion or in more than one portion. The addition isspecifically carried out at a temperature of below about 50° C., morespecifically at about 15° C. to about 35° C., and most specifically atabout 20° C. to about 30° C. under stirring. After completion of theaddition process, the resulting mass is heated and stirred at atemperature of about 50° C. to the reflux temperature of the solventused for at least 10 minutes, specifically at about 55° C. to about 100°C. for about 20 minutes to about 10 hours, and more specifically at atemperature of about 60° C. to about 90° C. for about 30 minutes toabout 4 hours to produce a second solution or suspension.

The second solution obtained in step-(b) is optionally subjected tocarbon treatment or silica gel treatment. The carbon treatment or silicagel treatment is carried out by methods known in the art, for example,by stirring the solution with finely powdered carbon or silica gel at atemperature of below about 70° C. for at least 15 minutes, specificallyat a temperature of about 40° C. to about 70° C. for at least 30minutes; and filtering the resulting mixture through hyflo to obtain afiltrate containing tapentadol acid addition salt by removing charcoalor silica gel. Specifically, the finely powdered carbon is an activecarbon. A specific mesh size of silica gel is 40-500 mesh, and morespecifically 60-120 mesh.

The isolation of pure solid state form of tapentadol salt in step-(c) iscarried out by crystallization, substantial removal of the solvent fromthe solution or suspension, or a combination thereof.

Crystallization may be initiated by a method usually known in the artsuch as cooling, seeding, partial removal of the solvent from thesolution, by adding an anti-solvent to the solution or a combinationthereof.

The term “anti-solvent” refers to a solvent which when added to anexisting solution of a substance reduces the solubility of thesubstance.

Exemplary anti-solvents include, but are not limited to, a hydrocarbon,an ether, and mixtures thereof. Specifically, the anti-solvent isselected from the group consisting of n-pentane, n-hexane, n-heptane,cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether,diisopropyl ether, monoglyme, diglyme, and mixtures thereof; and mostspecifically diethyl ether, diisopropyl ether, and mixtures thereof.

In one embodiment, the crystallization is carried out by cooling thesolution while stirring at a temperature of below 30° C. for at least 10minutes, specifically at about 0° C. to about 25° C. for about 30minutes to about 20 hours.

The term “substantially removing” the solvent refers to at least 80%,specifically greater than about 85%, more specifically greater thanabout 90%, still more specifically greater than about 99%, and mostspecifically essentially complete (100%), removal of the solvent fromthe second solution or suspension.

Removal of solvent is accomplished, for example, by substantiallycomplete evaporation of the solvent, concentrating the solution ordistillation of solvent, under inert atmosphere to obtain solid stateform of tapentadol salt.

In one embodiment, the solvent is removed by evaporation. Evaporationcan be achieved at sub-zero temperatures by lyophilisation orfreeze-drying techniques. The solution may also be completely evaporatedin, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in aconventional reactor under vacuum above about 720 mm Hg by flashevaporation techniques by using an agitated thin film dryer (“ATFD”), orevaporated by spray drying to obtain a dry amorphous powder.

The distillation process can be performed at atmospheric pressure orreduced pressure. Specifically, the solvent is removed at a pressure ofabout 760 mm Hg or less, more specifically at about 400 mm Hg or less,still more specifically at about 80 mm Hg or less, and most specificallyfrom about 30 to about 80 mm Hg.

Solvents can also be removed by spray-drying, in which a solution oftapentadol salt is sprayed into the spray drier at the flow rate of 10to 300 ml/hr, specifically 40 to 200 ml/hr. The air inlet temperature tothe spray drier used is about 30° C. to about 150° C., specificallyabout 65° C. to about 110° C. and the outlet air temperature used isabout 30° C. to about 90° C.

Another suitable method is vertical agitated thin-film drying (orevaporation). Agitated thin film evaporation technology involvesseparating the volatile component using indirect heat transfer coupledwith mechanical agitation of the flowing film under controlledconditions. In vertical agitated thin-film drying (or evaporation)(ATFD-V), the starting solution is fed from the top into a cylindricalspace between a centered rotary agitator and an outside heating jacket.The rotor rotation agitates the downside-flowing solution while theheating jacket heats it.

The recovery in step-(c) is carried out by methods such as filtration,filtration under vacuum, decantation, centrifugation, or a combinationthereof. In one embodiment, the solid state form of tapentadol salt isrecovered by filtration employing a filtration media of, for example, asilica gel or celite.

The substantially pure solid state form of tapentadol salt obtained byabove process may be further dried in, for example, a Vacuum tray dryer,a Rotocon vacuum dryer, a Vacuum paddle dryer or a pilot plant Rotavapor, to further lower residual solvents. Drying can be carried outunder reduced pressure until the residual solvent content reduces to thedesired amount such as an amount within the limits given by theInternational Conference on Harmonization of Technical Requirements forRegistration of Pharmaceuticals for human use (ICH) guide lines.

In one embodiment the drying is carried out at atmospheric pressure orreduced pressures, such as below about 200 mm Hg, or below about 50 mmHg, at temperatures such as 35° C. to about 80° C. The drying can becarried out for any desired time period that achieves the desiredresult, such as about 1 to 20 hours. Drying may also be carried out forshorter or longer periods of time depending on the productspecifications. Temperature and pressure are chosen based on thevolatility of the solvent being used and the foregoing should beconsidered as only a general guidance. Dying can be suitably carried outin a tray dryer, a vacuum oven, an air oven, or using a fluidized beddrier, a spin flash dyer, a flash dryer and the like. Drying equipmentselection is well within the ordinary skill in the art.

The solid state form of tapentadol salt obtained by the processdisclosed herein is further optionally converted into tapentadol freebase or its hydrochloride salt by treating the solid state form oftapentadol salt with a base and/or hydrochloric acid.

The treatment of the solid state form of tapentadol salt with a baseand/or an hydrochloric acid is carried out in a solvent selected fromthe group consisting of water, methanol, ethanol, n-propanol,isopropanol, n-butanol, isobutanol, tert-butanol, amyl alcohol, hexanol,acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butylketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate,tert-butyl methyl acetate, ethyl formate, dichloromethane,dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran,dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme,n-pentane, n-hexane, n-heptane, cyclohexane, to luene, xylene,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, andmixtures thereof.

The base suitable for converting the solid state form of tapentadol saltinto tapentadol free base or a pharmaceutically acceptable salt thereofis an organic or inorganic base. Specific organic bases are triethylamine, trimethylamine, N,N-diisopropylethylamine, N-methylmorpholine andN-methylpiperidine.

In another embodiment, the base is an inorganic base. Exemplaryinorganic bases include, but are not limited to, ammonia; hydroxides,alkoxides, carbonates and bicarbonates of alkali or alkaline earthmetals. Specific inorganic bases are ammonia, sodium hydroxide, calciumhydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, lithium carbonate, sodiumtert-butoxide, sodium isopropoxide and potassium tert-butoxide, and morespecifically ammonia, sodium hydroxide, potassium hydroxide, sodiumcarbonate and potassium carbonate.

The hydrochloric acid used may be in the form of concentratedhydrochloric acid, aqueous hydrochloric acid, in the form of hydrogenchloride gas, or hydrogen chloride dissolved in an organic solvent. Theorganic solvent used for dissolving hydrogen chloride gas or hydrogenchloride is selected from the group consisting of ethanol, methanol,isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether,acetone, and mixtures thereof.

Further encompassed herein is the use of the solid state form of atapentadol salt for the manufacture of a pharmaceutical compositiontogether with a pharmaceutically acceptable carrier, wherein the salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartratesalt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

A specific pharmaceutical composition of the solid state form oftapentadol salt is selected from a solid dosage form and an oralsuspension.

In one embodiment, the solid state form of tapentadol salt has a D₉₀particle size of less than or equal to about 500 microns, specificallyabout 1 micron to about 300 microns, and most specifically about 10microns to about 150 microns, wherein the salt of tapentadol is anL-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, adibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

In another embodiment, the particle sizes of the solid state form oftapentadol salt are produced by a mechanical process of reducing thesize of particles which includes any one or more of cutting, chipping,crushing, milling, grinding, micronizing, trituration or other particlesize reduction methods known in the art, to bring the solid state formto the desired particle size range.

According to another aspect, there is provided pharmaceuticalcompositions comprising the solid state form of tapentadol salt and oneor more pharmaceutically acceptable excipients, wherein the salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartratesalt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

According to another aspect, there is provided pharmaceuticalcompositions comprising the solid state form of tapentadol salt preparedaccording to process disclosed herein and one or more pharmaceuticallyacceptable excipients, wherein the salt of tapentadol is anL-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, adibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

According to another aspect, there is provided a process for preparing apharmaceutical formulation comprising combining the solid state form oftapentadol salt prepared according to processes disclosed herein, withone or more pharmaceutically acceptable excipients, wherein the salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartratesalt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

According to another aspect, there is provided a method for treating apatient suffering from severe acute pain; comprising administering asolid state form of tapentadol salt, or a pharmaceutical compositionthat comprises the solid state form of tapentadol salt along withpharmaceutically acceptable excipients, wherein the salt of tapentadolis an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartrate salt, adibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

Yet in another embodiment, pharmaceutical compositions comprise at leasta therapeutically effective amount of solid state form of a tapentadolsalt, wherein the salt of tapentadol is an L-(−)-camphorsulfonate salt,a dibenzoyl-(L)-tartrate salt, a dibenzoyl-(D)-tartrate salt, a malatesalt, a maleate salt or a salicylate salt. Such pharmaceuticalcompositions may be administered to a mammalian patient in a dosageform, e.g., solid, liquid, powder, elixir, aerosol, syrups, injectablesolution, etc. Dosage forms may be adapted for administration to thepatient by oral, buccal, parenteral, ophthalmic, rectal and transdermalroutes or any other acceptable route of administration. Oral dosageforms include, but are not limited to, tablets, pills, capsules, syrup,troches, sachets, suspensions, powders, lozenges, elixirs and the like.The solid state form of tapentadol salt may also be administered assuppositories, ophthalmic ointments and suspensions, and parenteralsuspensions, which are administered by other routes, wherein the salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(L)-tartratesalt, a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt or asalicylate salt.

The pharmaceutical compositions further contain one or morepharmaceutically acceptable excipients. Suitable excipients and theamounts to use may be readily determined by the formulation scientistbased upon experience and consideration of standard procedures andreference works in the field, e.g., the buffering agents, sweeteningagents, binders, diluents, fillers, lubricants, wetting agents anddisintegrants described herein.

In one embodiment, capsule dosage forms contain solid state form oftapentadol salt within a capsule which may be coated with gelatin.Tablets and powders may also be coated with an enteric coating. Suitableenteric coating include phthalic acid cellulose acetate,hydroxypropylmethyl cellulose phthalate, polyvinyl alcohol phthalate,carboxy methyl ethyl cellulose, a copolymer of styrene and maleic acid,a copolymer of methacrylic acid and methyl methacrylate, and likematerials, and if desired, the coating agents may be employed withsuitable plasticizers and/or extending agents. A coated capsule ortablet may have a coating on the surface thereof or may be a capsule ortablet comprising a powder or granules with an enteric-coating.

Tableting compositions may have few or many components depending uponthe tableting method used, the release rate desired and other factors.For example, the compositions described herein may contain diluents suchas cellulose-derived materials such as powdered cellulose,microcrystalline cellulose, microfine cellulose, methyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, carboxymethyl cellulose salts and othersubstituted and unsubstituted celluloses; starch; pregelatinized starch;inorganic diluents such as calcium carbonate and calcium diphosphate andother diluents known to one of ordinary skill in the art. Yet othersuitable diluents include waxes, sugars (e.g. lactose) and sugaralcohols such as mannitol and sorbitol, acrylate polymers andcopolymers, as well as pectin, dextrin and gelatin.

Other excipients include binders, such as acacia gum, pregelatinizedstarch, sodium alginate, glucose and other binders used in wet and drygranulation and direct compression tableting processes; disintegrantssuch as sodium starch glycolate, crospovidone, low-substitutedhydroxypropyl cellulose and others; lubricants like magnesium andcalcium stearate and sodium stearyl fumarate; flavorings; sweeteners;preservatives; pharmaceutically acceptable dyes and glidants such assilicon dioxide.

Instrumental Details: High Pressure Liquid Chromatography:

The HPLC purity was measured by high performance liquid chromatographyby using Waters, alliance 2695 HPLC system having dual wavelength and2487 UV detector under the following conditions:

Column ACE-3-C18, 150 * 4.6 mm, Part Number-ACE-111-1546. Column oventemperature 25° C. Detection UV at 237 nm and 210 nm Flow rate 1.0mL/minute Injection volume 10 μL Run time 55 minutes DiluentsWater:acetonitrile (50:50 v/v) Sample concentration Prepare a mixture of2.0 mg/ml of sample in diluents.

X-Ray Powder Diffraction (P-XRD):

The X-Ray powder diffraction was measured by an X-ray powderdiffractometer equipped with CuKα-radiations (40 kV, 40 mA) inwide-angle X-ray diffractometer of BRUKER axs, D8 ADVANCE. The samplewas analyzed using the following instrument parameters: measuringrange=3-45° 2-theta; step width=0.01579°; and measuring time perstep=0.11 sec.

Differential Scanning calorimetry (DSC):

Differential Scanning calorimetry (DSC) measurements were performed witha Differential Scanning calorimeter (DSC Q 1000 V23.5 Build 72,Universal V4.3A TA Instruments) at a scan rate of 5° C. per minute.

REFERENCE EXAMPLE Preparation of Tapentadol Hydrochloride Salt as perthe Process Disclosed in U.S. Pat. No. 6,248,737

Tapentadol free base (2.1 g) was added to 2-butanone (32 ml), themixture was heated to reflux and followed by the addition of water (0.22ml) and trimethylchlorosilane (1.6 ml) at the same temperature and thenmaintaining for 1 hour. The resulting mass was cooled at 20-25° C. Theresulting solid was filtered, the product was washed with pre-cooled2-butanone (4 ml) and then the solid was dried at 25° C. for 3 hours toproduce 1.8 g of tapentadol hydrochloride salt (Purity by HPLC: 97.78%).

The following examples are given for the purpose of illustrating thepresent disclosure and should not be considered as limitation on thescope or spirit of the disclosure.

EXAMPLES Example 1 Preparation of Solid State Form of TapentadolL-(−)-Camphorsulfonate Salt

Tapentadol (2 g) was dissolved in isopropyl alcohol (20 ml), followed bythe addition of (L)-camphorsulfonic acid (2.5 g) to the solution at25-30° C. and heating the reaction mass at 70-75° C. The resultingsolution was slowly cooled to 20-25° C. and stirred for 2 hours at20-25° C. The resulting solid was filtered, washed with isopropylalcohol (5 ml) and dried at 40-45° C. under vacuum to give 0.6 g oftapentadol L-(−)-camphorsulfonate salt.

Example 2 Preparation of Solid State Form of TapentadolDibenzoyl-(L)-Tartrate Salt

Tapentadol (2 g) was dissolved in isopropyl alcohol (20 ml), followed bythe addition of dibenzoyl-(L)-tartaric acid (4 g) to the solution at25-30° C. and heating the reaction mass at 80-85° C. The resultingsolution was slowly cooled to 20-25° C. and stirred for 2 hours at20-25° C. The resulting solid was collected by filtration, washed withisopropyl alcohol (5 ml) and dried at 40-45° C. under vacuum to give 1.2g of tapentadol dibenzoyl-(L)-tartrate salt (Purity by HPLC: 99.7%).

Example 3 Preparation of Solid State Form of TapentadolDibenzoyl-(D)-Tartrate Salt

Isopropyl alcohol (25 ml) was added to dibenzoyl-(D)-tartaric acid (7g), the mixture was stirred for 20 minutes and followed by the additionof a solution of tapentadol free base (4 g) in isopropyl alcohol (15 ml)at 25-30° C. The resulting solution was stirred for 15 minutes, followedby heating at 80° C. and then stirring for 15 minutes. The resultingmass was slowly cooled to 20-25° C. and stirred for 12 hours. Theresulting solid was filtered, washed with isopropyl alcohol (4 ml) andthen the solid was dried at 40° C. under vacuum for 6 hours to produce7.3 g of tapentadol dibenzoyl-(D)-tartrate salt (Purity by HPLC:99.68%).

Example 4 Preparation of Solid State Form of Tapentadol (DL)-Malate Salt

Tapentadol (2 g) was dissolved in isopropyl alcohol (15 ml), followed bythe addition of (d1)-malic acid (1.45 g) to the solution at 25-30° C.and heating the reaction mass at 80-85° C. The resulting solution wasslowly cooled to 20-25° C. and stirred for 2 hours at 20-25° C. Theresulting solid was collected by filtration, washed with isopropylalcohol (5 ml) and dried at 40-45° C. under vacuum to give 0.8 g oftapentadol (DL)-malate salt.

Example 5 Preparation of Solid State Form of Tapentadol Maleate Salt

Tapentadol (2 g) was dissolved in acetonitrile (15 ml), followed byaddition of maleic acid (1.25 g) to the solution at 25-30° C. andheating the reaction mass at 80-85° C. The resulting solution was slowlycooled to 20-25° C. and stirred for 2 hours at 20-25° C. The resultingsolid was collected by filtration, washed with acetonitrile (5 ml) anddried at 40-45° C. under vacuum to give 0.5 g of tapentadol maleatesalt.

Example 6 Preparation of Solid State Form of Tapentadol Salicylate Salt

Tapentadol (2 g) was dissolved in acetonitrile (15 ml), followed byaddition of salicylic acid (1.25 g) to the solution at 25-30° C. andheating the reaction mass at 80-85° C. The resulting solution was slowlycooled to 20-25° C. and stirred for 2 hours at 20-25° C. The resultingsolid was collected by filtration, washed with acetonitrile (10 ml) anddried at 40-45° C. under vacuum to give 2.5 g of tapentadol salicylatesalt (Purity by HPLC: 99.75%).

Unless otherwise indicated, the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

The term “solid state form of tapentadol salts disclosed herein”includes crystalline forms, amorphous form, hydrated, and solvated formsof tapentadol salts.

The term “crystalline form” refers to a crystal modification that can becharacterized by analytical methods such as X-ray powder diffraction,IR-spectroscopy, differential scanning calorimetry (DSC) or by itsmelting point.

The term “pharmaceutically acceptable” means that which is useful inpreparing a pharmaceutical composition that is generally non-toxic andis not biologically undesirable, and includes that which is acceptablefor veterinary use and/or human pharmaceutical use.

The term “pharmaceutical composition” is intended to encompass a drugproduct including the active ingredient(s), pharmaceutically acceptableexcipients that make up the carrier, as well as any product whichresults, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients. Accordingly, thepharmaceutical compositions encompass any composition made by admixingthe active ingredient, active ingredient dispersion or composite,additional active ingredient(s), and pharmaceutically acceptableexcipients.

The term “therapeutically effective amount” as used herein means theamount of a compound that, when administered to a mammal for treating astate, disorder or condition, is sufficient to effect such treatment.The “therapeutically effective amount” will vary depending on thecompound, the disease and its severity and the age, weight, physicalcondition and responsiveness of the mammal to be treated.

The term “delivering” as used herein means providing a therapeuticallyeffective amount of an active ingredient to a particular location withina host causing a therapeutically effective blood concentration of theactive ingredient at the particular location. This can be accomplished,e.g., by topical, local or by systemic administration of the activeingredient to the host.

The term “buffering agent” as used herein is intended to mean a compoundused to resist a change in pH upon dilution or addition of acid ofalkali. Such compounds include, by way of example and withoutlimitation, potassium metaphosphate, potassium phosphate, monobasicsodium acetate and sodium citrate anhydrous and dihydrate and other suchmaterial known to those of ordinary skill in the art.

The term “sweetening agent” as used herein is intended to mean acompound used to impart sweetness to a formulation. Such compoundsinclude, by way of example and without limitation, aspartame, dextrose,glycerin, mannitol, saccharin sodium, sorbitol, sucrose, fructose andother such materials known to those of ordinary skill in the art.

The term “binders” as used herein is intended to mean substances used tocause adhesion of powder particles in granulations. Such compoundsinclude, by way of example and without limitation, acacia, alginic acid,tragacanth, carboxymethylcellulose sodium, polyvinylpyrrolidone,compressible sugar (e.g., NuTab), ethylcellulose, gelatin, liquidglucose, methylcellulose, pregelatinized starch, starch, polyethyleneglycol, guar gum, polysaccharide, bentonites, sugars, invert sugars,poloxamers (PLURONIC(™) F68, PLURONIC(™) F127), collagen, albumin,celluloses in non-aqueous solvents, polypropylene glycol,polyoxyethylene-polypropylene copolymer, polyethylene ester,polyethylene sorbitan ester, polyethylene oxide, microcrystallinecellulose, combinations thereof and other material known to those ofordinary skill in the art.

The term “diluent” or “filler” as used herein is intended to mean inertsubstances used as fillers to create the desired bulk, flow properties,and compression characteristics in the preparation of solid dosageformulations. Such compounds include, by way of example and withoutlimitation, dibasic calcium phosphate, kaolin, sucrose, mannitol,microcrystalline cellulose, powdered cellulose, precipitated calciumcarbonate, sorbitol, starch, combinations thereof and other suchmaterials known to those of ordinary skill in the art.

The term “glidant” as used herein is intended to mean agents used insolid dosage formulations to improve flow-properties during tabletcompression and to produce an anti-caking effect. Such compoundsinclude, by way of example and without limitation, colloidal silica,calcium silicate, magnesium silicate, silicon hydrogel, cornstarch,talc, combinations thereof and other such materials known to those ofordinary skill in the art.

The term “lubricant” as used herein is intended to mean substances usedin solid dosage formulations to reduce friction during compression ofthe solid dosage. Such compounds include, by way of example and withoutlimitation, calcium stearate, magnesium stearate, mineral oil, stearicacid, zinc stearate, combinations thereof and other such materials knownto those of ordinary skill in the art.

The term “disintegrant” as used herein is intended to mean a compoundused in solid dosage formulations to promote the disruption of the solidmass into smaller particles which are more readily dispersed ordissolved. Exemplary disintegrants include, by way of example andwithout limitation, starches such as corn starch, potato starch,pregelatinized, sweeteners, clays, such as bentonite, microcrystallinecellulose (e.g., Avicel(™)), carsium (e.g., Amberlite(™)), alginates,sodium starch glycolate, gums such as agar, guar, locust bean, karaya,pectin, tragacanth, combinations thereof and other such materials knownto those of ordinary skill in the art.

The term “wetting agent” as used herein is intended to mean a compoundused to aid in attaining intimate contact between solid particles andliquids. Exemplary wetting agents include, by way of example and withoutlimitation, gelatin, casein, lecithin (phosphatides), gum acacia,cholesterol, tragacanth, stearic acid, benzalkonium chloride, calciumstearate, glycerol monostearate, cetostearyl alcohol, cetomacrogolemulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g.,macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oilderivatives, polyoxyethylene sorbitan fatty acid esters, (e.g.,TWEEN(™)s), polyethylene glycols, polyoxyethylene stearates colloidalsilicon dioxide, phosphates, sodium dodecylsulfate,carboxymethylcellulose calcium, carboxymethylcellulose sodium,methylcellulo se, hydroxyethylcellulose, hydroxyl propylcellulose,hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, andpolyvinylpyrrolidone (PVP). Tyloxapol (a nonionic liquid polymer of thealkyl aryl polyether alcohol type) is another useful wetting agent,combinations thereof and other such materials known to those of ordinaryskill in the art.

The term “micronization” used herein means a process or method by whichthe size of a population of particles is reduced.

As used herein, the term “micron” or “gm” both are same refers to“micrometer” which is 1×10⁻⁶ meter.

As used herein, “crystalline particles” means any combination of singlecrystals, aggregates and agglomerates.

As used herein, “Particle Size Distribution (P.S.D)” means thecumulative volume size distribution of equivalent spherical diameters asdetermined by laser diffraction in Malvern Master Sizer 2000 equipmentor its equivalent.

The important characteristics of the PSD are the (D₉₀), which is thesize, in microns, below which 90% of the particles by volume are found,and the (D₅₀), which is the size, in microns, below which 50% of theparticles by volume are found. Thus, a D₉₀ or d(0.9) of less than 300microns means that 90 volume-percent of the particles in a compositionhave a diameter less than 300 microns.

The use of the terms “a” and “an” and “the” and similar referents in thecontext of describing the invention (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1. Solid state form of a salt of3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (tapentadolsalt), wherein the salt of tapentadol is an L-(−)-camphorsulfonate salt,a dibenzoyl-(D)-tartrate salt, a malate salt, a maleate salt, or asalicylate salt.
 2. The solid state form of tapentadol salt of claim 1,which is in a crystalline form or in an amorphous form, and wherein thesolid state form is anhydrous and/or solvent-free form, or a hydrateand/or a solvate form.
 3. The solid state form of tapentadol salt ofclaim 1, having the following characteristics, wherein: a) the solidstate form of tapentadol L-(−)-camphorsulfonate salt is characterized byone or more of the following properties: i) a powder X-ray diffractionpattern substantially in accordance with FIG. 1; ii) a powder X-raydiffraction pattern having peaks at about 3.93, 5.66, 14.94, 16.16 and21.52±0.2 degrees 2-theta; iii) a powder X-ray diffraction patternhaving additional peaks at about 8.01, 11.36, 14.10, 15.27, 15.91,16.72, 19.06, 19.88, 21.85, 22.56, 23.92 and 27.12±0.2 degrees 2-theta;and iv) a differential scanning calorimetric (DSC) thermogramsubstantially in accordance with FIG. 2; b) the solid state form oftapentadol dibenzoyl-(D)-tartrate salt is characterized by one or moreof the following properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 5; ii) a powder X-ray diffractionpattern having peaks at about 8.52, 9.39, 11.81, 12.28, 13.46, 14.06,17.77, 17.97, 18.33, 18.79, 19.58 and 20.05±0.2 degrees 2-theta; iii) apowder X-ray diffraction pattern having additional peaks at about 10.69,11.61, 14.76, 21.41, 21.66, 22.19, 22.96, 23.23, 24.38, 25.72, 26.42,27.60, 27.82, 28.29, 28.46 and 30.65±0.2 degrees 2-theta; and iv) adifferential scanning calorimetric (DSC) thermogram substantially inaccordance with FIG. 6; c) the solid state form of tapentadol malatesalt is characterized by one or more of the following properties: i) apowder X-ray diffraction pattern substantially in accordance with FIG.7; ii) a powder X-ray diffraction pattern having peaks at about 9.80,19.74, 20.27, 22.87 and 24.85±0.2 degrees 2-theta; iii) a powder X-raydiffraction pattern having additional peaks at about 17.63, 22.56,26.30, 26.74, 30.67, 31.15, 33.73, 34.12, 35.89, 38.19, 39.27, 41.27 and43.44 ±0.2 degrees 2-theta; and iv) a differential scanning calorimetric(DSC) thermogram substantially in accordance with FIG. 8; d) the solidstate form of tapentadol maleate salt is characterized by one or more ofthe following properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 9; ii) a powder X-ray diffractionpattern having peaks at about 15.31, 16.08, 21.08, 27.95, 28.53 and29.51±0.2 degrees 2-theta; iii) a powder X-ray diffraction patternhaving peaks at about 19.13, 20.44, 22.90, 24.76, 30.66, 31.06, 31.81,33.80, 34.84, 35.29, 38.31, 40.26, 40.68 and 43.16±0.2 degrees 2-theta;and iv) a differential scanning calorimetric (DSC) thermogramsubstantially in accordance with FIG. 10; e) the solid state form oftapentadol salicylate salt is characterized by one or more of thefollowing properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 11; ii) a powder X-ray diffractionpattern having peak at about 12.42, 12.75, 13.98, 15.37 and 19.81±0.2degrees 2-theta; iii) a powder X-ray diffraction pattern having peak atabout 16.39, 19.31, 21.06, 21.41, 21.98, 24.85, 25.03, 25.45, 26.54 and27.88±0.2 degrees 2-theta; and iv) a differential scanning calorimetric(DSC) thermogram substantially in accordance with FIG.
 12. 4. A processfor the preparation of a solid state form of a salt of3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol (tapentadolsalt), wherein the salt of tapentadol is an L-(−)-camphorsulfonate salt,a dibenzoyl-(L)-tartrate salt, a dibenzoyl-(D)-tartrate salt, a malatesalt, a maleate salt, or a salicylate salt, comprising: a) providing afirst solution or a suspension of tapentadol free base in a solvent,wherein the solvent is water, an alcohol, a ketone, a nitrile, a polaraprotic solvent, or a mixture thereof; b) combining the first solutionor suspension with an acid to produce a second solution or suspensioncontaining a tapentadol acid addition salt, wherein the acid is selectedfrom the group consisting of L-(−)-camphorsulfonic acid,dibenzoyl-(L)-tartaric acid, dibenzoyl-(D)-tartaric acid, malic acid,maleic acid and salicylic acid; and c) isolating and/or recovering thesolid state form of the tapentadol salt from the second solution orsuspension obtained in step-(b).
 5. The process of claim 4, wherein thesolvent used in step-(a) is selected from the group consisting of water,methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol,tert-butanol, amyl alcohol, isoamyl alcohol, hexanol, acetone, methylethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone,acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,dimethylsulfoxide, and mixtures thereof.
 6. The process of claim 5,wherein the solvent is selected from the group consisting of water,methanol, ethanol, isopropyl alcohol, acetonitrile, and mixturesthereof.
 7. The process of claim 4, wherein the first solution instep-(a) is prepared by dissolving tapentadol free base in the solventat a temperature of below about boiling temperature of the solvent used;wherein the suspension in step-(a) is provided by suspending tapentadolfree base in the solvent while stirring at a temperature of about 0° C.to the reflux temperature of the solvent used; wherein the firstsolution or suspension obtained in step-(a) is optionally stirred at atemperature of about 25° C. to the reflux temperature of the solvent forabout 20 minutes to about 5 hours; wherein the combining in step-(b) isaccomplished by adding the first solution or suspension to the acid orby adding the acid to the first solution or suspension, at a temperatureof below about 50° C.; wherein the reaction mass obtained aftercompletion of the addition process in step-(b) is stirred at atemperature of about 50° C. to the reflux temperature of the solvent forat least 10 minutes to produce a second solution or suspension; whereinthe second solution obtained in step-(b) is optionally subjected tocarbon treatment or silica gel treatment; wherein the isolation of puresolid state form of tapentadol salt in step-(c) is carried out bycrystallization, substantial removal of the solvent from the solution orsuspension, or a combination thereof; wherein the recovering in step-(c)is carried out by filtration, filtration under vacuum, decantation,centrifugation, filtration employing a filtration media of a silica gelor celite, or a combination thereof; and wherein the substantially puresolid state form of tapentadol salt obtained is further dried undervacuum or at atmospheric pressure, at a temperature of about 35° C. toabout 80° C.
 8. The process of claim 7, wherein the tapentadol free baseis dissolved in the solvent at a temperature of about 20° C. to about110° C.; wherein the suspension is stirred at a temperature of about 20°C. to about 110° C. for at least 30 minutes; wherein the addition instep-(b) is carried out at a temperature of about 15° C. to about 35°C.; wherein the reaction mass obtained after completion of the additionprocess in step-(b) is stirred at a temperature of about 55° C. to about100° C. for about 20 minutes to about 10 hours; wherein thecrystallization is initiated by cooling, seeding, partial removal of thesolvent from the solution, by adding an anti-solvent to the solution, ora combination thereof; and wherein the removal of solvent isaccomplished by substantially complete evaporation of the solvent,concentrating the solution or distillation of solvent under inertatmosphere, spray drying, vacuum drying, agitated thin-film (ATFD)drying, or a combination thereof.
 9. The process of claim 8, wherein thecrystallization is carried out by cooling the solution while stirring ata temperature of about 0° C. to about 30° C. for about 10 minutes toabout 20 hours; and wherein the anti-solvent is selected from the groupconsisting of n-pentane, n-hexane, n-heptane, cyclohexane, toluene,xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,monoglyme, diglyme, and mixtures thereof.
 10. (canceled)
 11. The processof claim 4, wherein the solid state form of tapentadol salt obtained isoptionally converted into tapentadol free base or its hydrochloride saltby treating the solid state form of tapentadol salt with a base and/orhydrochloric acid in a solvent.
 12. The process of claim 11, wherein thesolvent is selected from the group consisting of water, methanol,ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol,amyl alcohol, hexanol, acetone, methyl ethyl ketone, methyl isobutylketone, methyl tert-butyl ketone, acetonitrile, ethyl acetate, methylacetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme,diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene,N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, andmixtures thereof; wherein the base is an organic or inorganic baseselected from the group consisting of triethyl amine, trimethylamine,N,N-diisopropylethylamine, N-methylmorpholine, N-methylpiperidine,ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxideand potassium tert-butoxide; and wherein the hydrochloric acid is usedin the form of concentrated hydrochloric acid, aqueous hydrochloricacid, in the form of hydrogen chloride gas, or hydrogen chloridedissolved in an organic solvent selected from the group consisting ofethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether,dimethyl ether, acetone, and mixtures thereof.
 13. A pharmaceuticalcomposition comprising a solid state form of a tapentadol salt and oneor more pharmaceutically acceptable excipients, wherein the salt oftapentadol is an L-(−)-camphorsulfonate salt, a dibenzoyl-(D)-tartratesalt, a malate salt, a maleate salt or a salicylate salt.
 14. Thepharmaceutical composition of claim 13, wherein the pharmaceuticalcomposition is a solid dosage form, an oral suspension, a liquid, apowder, an elixir, an aerosol, a syrup, or an injectable solution. 15.The pharmaceutical composition of claim 13, wherein the solid state formof tapentadol salt has a D₉₀ particle size of less than or equal toabout 500 microns.
 16. The pharmaceutical composition of claim 15,wherein the D₉₀ particle size is about 1 micron to about 300 microns, orabout 10 microns to about 150 microns.
 17. (canceled)
 18. The process ofclaim 4, wherein the solid state form of tapentadol salt has thefollowing characteristics, wherein: a) the solid state form oftapentadol L-(−)-camphorsulfonate salt is characterized by one or moreof the following properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 1; ii) a powder X-ray diffractionpattern having peaks at about 3.93, 5.66, 14.94, 16.16 and 21.52±0.2degrees 2-theta; iii) a powder X-ray diffraction pattern havingadditional peaks at about 8.01, 11.36, 14.10, 15.27, 15.91, 16.72,19.06, 19.88, 21.85, 22.56, 23.92 and 27.12±0.2 degrees 2-theta; and iv)a differential scanning calorimetric (DSC) thermogram substantially inaccordance with FIG. 2; b) the solid state form of tapentadoldibenzoyl-(L)-tartrate salt is characterized by one or more of thefollowing properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 3; ii) a powder X-ray diffractionpattern having peaks at about 4.83, 5.76, 9.61, 16.08, 17.40 and17.82±0.2 degrees 2-theta; iii) a powder X-ray diffraction patternhaving additional peaks at about 11.72, 13.26, 14.39, 17.19, 18.14,18.90, 19.19, 20.88, 21.53, 21.88, 22.43, 22.78, 23.31, 23.53, 24.06,26.58, 27.26, 27.98, 31.22, 34.75 and 34.96±0.2 degrees 2-theta; and iv)a differential scanning calorimetric (DSC) thermogram substantially inaccordance with FIG. 4; c) the solid state form of tapentadoldibenzoyl-(D)-tartrate salt is characterized by one or more of thefollowing properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 5; ii) a powder X-ray diffractionpattern having peaks at about 8.52, 9.39, 11.81, 12.28, 13.46, 14.06,17.77, 17.97, 18.33, 18.79, 19.58 and 20.05±0.2 degrees 2-theta; iii) apowder X-ray diffraction pattern having additional peaks at about 10.69,11.61, 14.76, 21.41, 21.66, 22.19, 22.96, 23.23, 24.38, 25.72, 26.42,27.60, 27.82, 28.29, 28.46 and 30.65±0.2 degrees 2-theta; and iv) adifferential scanning calorimetric (DSC) thermogram substantially inaccordance with FIG. 6; d) the solid state form of tapentadol malatesalt is characterized by one or more of the following properties: i) apowder X-ray diffraction pattern substantially in accordance with FIG.7; ii) a powder X-ray diffraction pattern having peaks at about 9.80,19.74, 20.27, 22.87 and 24.85±0.2 degrees 2-theta; iii) a powder X-raydiffraction pattern having additional peaks at about 17.63, 22.56,26.30, 26.74, 30.67, 31.15, 33.73, 34.12, 35.89, 38.19, 39.27, 41.27 and43.44 ±0.2 degrees 2-theta; and iv) a differential scanning calorimetric(DSC) thermogram substantially in accordance with FIG. 8; e) the solidstate form of tapentadol maleate salt is characterized by one or more ofthe following properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 9; i) a powder X-ray diffractionpattern having peaks at about 15.31, 16.08, 21.08, 27.95, 28.53 and29.51±0.2 degrees 2-theta; iii) a powder X-ray diffraction patternhaving peaks at about 19.13, 20.44, 22.90, 24.76, 30.66, 31.06, 31.81,33.80, 34.84, 35.29, 38.31, 40.26, 40.68 and 43.16±0.2 degrees 2-theta;and iv) a differential scanning calorimetric (DSC) thermogramsubstantially in accordance with FIG. 10; f) the solid state form oftapentadol salicylate salt is characterized by one or more of thefollowing properties: i) a powder X-ray diffraction patternsubstantially in accordance with FIG. 11; ii) a powder X-ray diffractionpattern having peak at about 12.42, 12.75, 13.98, 15.37 and 19.81±0.2degrees 2-theta; iii) a powder X-ray diffraction pattern having peak atabout 16.39, 19.31, 21.06, 21.41, 21.98, 24.85, 25.03, 25.45, 26.54 and27.88±0.2 degrees 2-theta; and iv) a differential scanning calorimetric(DSC) thermogram substantially in accordance with FIG.
 12. 19. Theprocess of claim 5, wherein the solvent is selected from the groupconsisting of isopropyl alcohol and acetonitrile.